Our recent studies have indicated a critical role for the T-box transcription factor T-bet in the regulation of class switching in B cells as well as in autoantibody production in systemic autoimmune disease: T-bet deficiency dramatically impairs IFN-gamma-mediated class switching to IgG2a as well as the generation of autoantibodies in the MRL/Ipr murine model of lupus, and conversely enhances IL-4-related responses, such as IgE production. Using genetically mutant mice and in vitro cell culture systems, we propose here to further delineate the role of T-bet in both conventional and autoimmune B cell responses by defining and characterizing the molecular pathways in which this novel pathogenic and therapeutic target regulates isotype switching, cellular proliferation, and the activation of mature, autoreactive B lymphocytes. [unreadable] [unreadable]